Novel roles of an intragenic G-quadruplex in controlling microRNA expression and cardiac function

Nucleic Acids Res. 2021 Mar 18;49(5):2522-2536. doi: 10.1093/nar/gkab055.


Simultaneous dysregulation of multiple microRNAs (miRs) affects various pathological pathways related to cardiac failure. In addition to being potential cardiac disease-specific markers, miR-23b/27b/24-1 were reported to be responsible for conferring cardiac pathophysiological processes. In this study, we identified a conserved guanine-rich RNA motif within the miR-23b/27b/24-1 cluster that can form an RNA G-quadruplex (rG4) in vitro and in cells. Disruption of this intragenic rG4 significantly increased the production of all three miRs. Conversely, a G4-binding ligand tetrandrine (TET) stabilized the rG4 and suppressed miRs production in human and rodent cardiomyocytes. Our further study showed that the rG4 prevented Drosha-DGCR8 binding and processing of the pri-miR, suppressing the biogenesis of all three miRs. Moreover, CRISPR/Cas9-mediated G4 deletion in the rat genome aberrantly elevated all three miRs in the heart in vivo, leading to cardiac contractile dysfunction. Importantly, loss of the G4 resulted in reduced targets for the aforementioned miRs critical for normal heart function and defects in the L-type Ca2+ channel-ryanodine receptor (LCC-RyR) coupling in cardiomyocytes. Our results reveal a novel mechanism for G4-dependent regulation of miR biogenesis, which is essential for maintaining normal heart function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzylisoquinolines / pharmacology
  • CRISPR-Cas Systems
  • Cells, Cultured
  • G-Quadruplexes* / drug effects
  • Gene Expression Regulation
  • MicroRNAs / chemistry*
  • MicroRNAs / metabolism*
  • Myocardial Contraction / genetics*
  • Myocardium / metabolism
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / physiology
  • RNA Processing, Post-Transcriptional
  • RNA-Binding Proteins / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Ribonuclease III / metabolism
  • Ryanodine Receptor Calcium Release Channel / metabolism


  • Benzylisoquinolines
  • MIRN23b microRNA, human
  • MIRN24 microRNA, human
  • MIRN24 microRNA, rat
  • MIRN27 microRNA, rat
  • MIRN27b microRNA, human
  • MicroRNAs
  • RNA-Binding Proteins
  • Ryanodine Receptor Calcium Release Channel
  • tetrandrine
  • Ribonuclease III